Status Epilepticus in Dogs and Cats, Part 1: Etiopathogenesis, Epidemiology, and Diagnosis

Status Epilepticus in Dogs and Cats, Part 1: Etiopathogenesis, Epidemiology, and Diagnosis

Clinical Practice Review Journal of Veterinary Emergency and Critical Care 27(3) 2017, pp 278–287 doi: 10.1111/vec.12605 Status epilepticus in dogs and cats, part 1: etiopathogenesis, epidemiology, and diagnosis Susan Blades Golubovic, DVM and John H. Rossmeisl Jr., DVM, MS, DACVIM Abstract Objective – To review current knowledge of the etiopathogenesis, diagnosis, and consequences of status epilep- ticus (SE) in veterinary patients. Data Sources – Human and veterinary literature, including clinical and laboratory research and reviews. Etiopathogenesis – Status epilepticus is a common emergency in dogs and cats, and may be the first manifes- tation of a seizure disorder. It results from the failure of termination of an isolated seizure. Multiple factors are involved in SE, including initiation and maintenance of neuronal excitability, neuronal network synchroniza- tion, and brain microenvironmental contributions to ictogenesis. Underlying etiologies of epilepsy and SE in dogs and cats are generally classified as genetic (idiopathic), structural-metabolic, or unknown. Diagnosis – Diagnosis of convulsive SE is usually made based on historical information and the nature of the seizures. Patient specific variables, such as the history, age of seizure onset, and physical and interictal neuro- logical examination findings can help hone the rule out list, and are used to guide selection and prioritization of diagnostic tests. Electroencephalographic monitoring is routinely used in people to diagnose SE and guide patient care decisions, but is infrequently performed in veterinary medicine. Nonconvulsive status epilepticus has been recognized in veterinary patients; routine electroencephalography would aid in the diagnosis of this phenomenon in dogs and cats. Clinical Sequelae – Status epilepticus is a medical emergency that can result in life-threatening complications involving the brain and systemic organs. Status epilepticus often requires comprehensive diagnostic testing, treatment with multiple anticonvulsant agents, and intensive supportive care. (J Vet Emerg Crit Care 2017; 27(3): 278–287) doi: 10.1111/vec.12605 Keywords: canine, central nervous system, epilepsy, feline, GABA, seizure Pgp P-glycoprotein Abbreviations SE status epilepticus COX cyclooxygenase SUDEP sudden unexpected death in epilepsy CSE convulsive status epilepticus EEG electroencephalogram GABA ␥-aminobutyric acid Introduction HRV heart rate variability An epileptic seizure is defined as hypersynchronous MRI magnetic resonance imaging neuronal electrical activity in the cerebral cortex that NCSE nonconvulsive status epilepticus manifests as a paroxysmal and transient abnormality NMDA N-methyl-D-aspartate of consciousness, motor activity, autonomic function, sensation, or cognition.1 Status epilepticus (SE) is com- monly defined as seizure activity that lasts for more than From the VCA Veterinary Referral Associates, 500 Perry Parkway, Gaithers- burg, MD 20877 (Golubovic); and the Department of Small Animal Clin- 5 minutes, or the occurrence of 2 or more seizures with- ical Sciences, Virginia-Maryland Regional College of Veterinary Medicine, out recovery of consciousness.1,2 Status epilepticus was Blacksburg, VA 24060 (Rossmeisl). initially defined as seizure activity that persisted for 20– The authors declare no conflicts of interest. 30 minutes, or the amount of time needed to cause irre- Address correspondence and reprint requests to Dr. Susan Blades Golubovic, versible neuronal damage or death. However, the def- VCA SouthPaws Veterinary Specialists and Emergency Care, 8500 Arlington Blvd. Fairfax, VA 22031, USA. Email: [email protected] inition has been refined as clinicians recognized that Submitted April 17, 2015; Accepted October 20, 2015. emergency treatment was necessary before 20 minutes 278 C Veterinary Emergency and Critical Care Society 2017 Status epilepticus: etiopathogenesis and diagnosis has passed.3 Status epilepticus is a life-threatening emer- tion occurs after the action potential burst, followed by gency that requires immediate intervention. Refractory rapid repolarization and then hyperpolarization that is status epilepticus is defined as SE that does not respond mediated by ␥-aminobutyric acid (GABA) receptors.14,15 to first-line anticonvulsant therapy.1,4 Superrefractory The excitability of neurons can be affected by alterations status epilepticus is defined as SE continuing or recur- in neurotransmitter receptor function or distribution; ring more than 24 hours after initiation of treatment with neurotransmitter synthesis, release, or recycling; energy anesthetic therapy.5 Not to be confused with SE, the con- metabolism; or ion channel function.16 Within minutes dition of acute repetitive seizures has been defined as the of initiation of seizure activity, persistent depolarization occurrence of 2 or more distinct seizures within a 24-hour within the affected cortical region causes profound and period with the patient regaining consciousness between gradual changes in local regulation. These changes are seizures. Acute repetitive seizures have also been called characterized by activation of second messenger sys- serial, repetitive, or crescendo seizures, and are most of- tems, altered gene expression and protein production, ten called cluster seizures in veterinary medicine.6,7 and reorganization of synapses. The end result is irre- Status epilepticus is a common neurologic emergency versible cell damage and death. As the seizure contin- in people and small animals. It has been estimated that ues, the epileptogenic region of the cortex can become 150,000 cases of SE occur each year in people living in refractory to anticonvulsant therapy.17 the United States, with 55,000 associated deaths and an It has been proposed that SE develops due to a fail- estimated cost of inpatient admission of $4 billion.4,8,9 In ure of inhibition or excessive stimulation. The major 1 veterinary study, the prevalence of dogs hospitalized inhibitory neurotransmitter is GABA. GABA receptors for seizure activity and SE was 2.6% and 0.7%, respec- are divided into 3 categories: GABA-A, GABA-B, and tively. Status epilepticus has been identified in 16.5% of GABA-A␳ (formerly known as GABA-C).18 Binding of dogs presenting to the hospital for seizure activity and GABA to GABA-A receptors causes chloride influx and was the first manifestation of a seizure disorder in 58% hyperpolarization of the cell, which inhibits future action of dogs.10,11 potentials. GABA-A agonists, such as benzodiazepines In dogs that present in SE, prompt treatment to stop and barbiturates, can terminate seizure activity. It has clinical and electrical seizure activity is necessary, as pro- been documented in recent years that the expression, lo- longed seizure activity has several negative systemic and cation, and number of GABA-A receptors is dynamic neurologic consequences. Status epilepticus of longer and tightly regulated. The GABA-B receptor is a G- duration is less responsive to anticonvulsant therapy protein coupled receptor. Ligand binding to GABA-B compared to SE of shorter duration.1 In addition to opens potassium channels and closes calcium channels, their potential to increase morbidity and mortality, clus- which leads to hyperpolarization of the membrane.4,19,20 ter seizures and SE are disturbing for pet owners to Studies in human and animal models have shown that witness.12,13 the inhibitory effect of GABA is altered with time, as drugsthatactatGABAreceptorsbecomelesseffective with prolonged seizure activity.2,3,21–25 The diminished efficacy of GABA agonists may be related to altered re- Pathophysiology of Status Epilepticus ceptor function or internalization of GABA receptors.4 In Status epilepticus results from a failure to terminate epileptic rats, the expression of GABA receptor mRNA seizure activity. The mechanisms that cause isolated and the function of GABA receptors was found to be seizure activity to progress to SE are unknown, likely abnormal.26 In mouse and rat models, SE resulted in multifactorial, and probably depend on the etiology of decreased stability of GABA-A receptor subunits and re- the seizure. Seizures result from spontaneous, excessive, duced GABA-A receptor cell surface expression, as well hypersynchronous electrical discharge from a group of as internalization and functional loss of GABA-A recep- neurons in cortical tissue. This discharge can begin in tors with prolonged SE.27,28 Further studies documented one region of the cortex and spread to neighboring re- decreased surface expression of the ␤2/3 and ␥2 GABA- gions. Any event that disrupts the balance between neu- A subunits.29 ronal excitation and inhibition can cause a seizure fo- The major excitatory neurotransmitters in the cen- cus to form. In an epileptic focus, neurons undergo a tral nervous system are glutamate, aspartate, and sequence of events known as the paroxysmal depolar- acetylcholine. The 2 main types of glutamate recep- ization shift. First, sustained and uninhibited neuronal tors are inotropic and metabotropic. Inotropic recep- depolarization may lead to the cellular influx of cal- tors include alpha-amino-2,3-dihydro-5-methyl-3-oxo-4- cium. The calcium influx leads to opening of voltage- isoxazolepropanoic acid (AMPA), kainate receptors, and gated sodium channels and an influx of sodium, causing N-methyl-D-aspartate (NMDA) receptors. The influx of a burst of action potentials. A plateau-like depolariza- sodium and the efflux of potassium through inotropic C Veterinary Emergency and Critical Care

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